Selective Oxidation of Alcohols to Carbonyls under Decatungstate-Mediated Photoelectrochemical Conditions.

The oxidation of alcohols to the corresponding carbonyl derivatives has been realized under photoelectrochemical conditions in the presence of tetrabutylammonium decatungstate (TBADT) as the homogeneous photocatalyst. The protocol can be applied to both primary and secondary, benzylic and aliphatic alcohols. The desired products are obtained selectively, skipping the need for purposely added chemical oxidants. An in-depth study of photoelectrochemical conditions revealed that the protocol works best under amperostatic conditions in an undivided electrochemical cell irradiated with a 390 nm LED lamp. The comparison with analogous electrochemical and chemical oxidant-promoted photocatalytic oxidations demonstrates the superior efficiency and selectivity of the hereby reported photoelectrochemical conditions.

Direct Photocatalyzed Hydrogen Atom Transfer (HAT) for Aliphatic C-H Bonds Elaboration.

Direct photocatalyzed hydrogen atom transfer (d-HAT) can be considered a method of choice for the elaboration of aliphatic C-H bonds. In this manifold, a photocatalyst (PCHAT) exploits the energy of a photon to trigger the homolytic cleavage of such bonds in organic compounds. Selective C-H bond elaboration may be achieved by a judicious choice of the hydrogen abstractor (key parameters are the electronic character and the molecular structure), as well as reaction additives. Different are the classes of PCsHAT available, including aromatic ketones, xanthene dyes (Eosin Y), polyoxometalates, uranyl salts, a metal-oxo porphyrin and a tris(amino)cyclopropenium radical dication. The processes (mainly C-C bond formation) are in most cases carried out under mild conditions with the help of visible light. The aim of this review is to offer a comprehensive survey of the synthetic applications of photocatalyzed d-HAT.

Photoinduced Halogen-Atom Transfer by N-Heterocyclic Carbene-Ligated Boryl Radicals for C(sp3)-C(sp3) Bond Formation.

Herein, we present a comprehensive study on the use of N-heterocyclic carbene (NHC)-ligated boryl radicals to enable C(sp3)-C(sp3) bond formation under visible-light irradiation via Halogen-Atom Transfer (XAT). The methodology relies on the use of an acridinium dye to generate the boron-centered radicals from the corresponding NHC-ligated boranes via single-electron transfer (SET) and deprotonation. These boryl radicals subsequently engage with alkyl halides in an XAT step, delivering the desired nucleophilic alkyl radicals. The present XAT strategy is very mild and accommodates a broad scope of alkyl halides, including medicinally relevant compounds and biologically active molecules. The key role of NHC-ligated boryl radicals in the operative reaction mechanism has been elucidated through a combination of experimental, spectroscopic, and computational studies. This methodology stands as a significant advancement in the chemistry of NHC-ligated boryl radicals, which had long been restricted to radical reductions, enabling C-C bond formation under visible-light photoredox conditions.

Accelerated Electrophotocatalytic C(sp3 )-H Heteroarylation Enabled by an Efficient Continuous-Flow Reactor.

Electrophotocatalytic transformations are garnering attention in organic synthesis, particularly for accessing reactive intermediates under mild conditions. Moving these methodologies to continuous-flow systems, or flow ElectroPhotoCatalysis (f-EPC), showcases potential for scalable processes due to enhanced irradiation, increased electrode surface, and improved mixing of the reaction mixture. Traditional methods sequentially link photochemical and electrochemical reactions, using flow reactors connected in series, yet struggle to accommodate reactive transient species. In this study, we introduce a new flow reactor concept for electrophotocatalysis (EPC) that simultaneously utilizes photons and electrons. The reactor is designed with a transparent electrode and employs cost-effective materials. We used this technology to develop an efficient process for electrophotocatalytic heteroarylation of C(sp3 )-H bonds. Importantly, the same setup can also facilitate purely electrochemical and photochemical transformations. This reactor represents a significant advancement in electrophotocatalysis, providing a framework for its application in flow for complex synthetic transformations.

Catalyst-free [2 + 2] photocycloadditions between benzils and olefins under visible light.

The catalyst-free [2 + 2] photocycloaddition between benzils and simple olefins is reported. The adoption of visible light proved essential for the transformation, as shorter wavelengths led to uncontrolled decomposition. When cyclic olefins were used, the reaction occurred smoothly to afford the expected oxetanes regio- and stereoselectively after 24 h of irradiation. In contrast, in the case of acyclic olefins, longer reaction times were typically required and small amounts (ca. 20%) of [4 + 2] photocycloadducts and by-products deriving from competitive hydrogen atom abstraction were observed. The selectivity of the transformation could be consistently improved by decreasing the reaction temperature, thus restoring the desired [2 + 2] reactivity. An overall mechanistic picture is also offered based on the chemical and photophysical quenching experiments and the stereochemical output is rationalized based on Griesbeck models.

Decatungstate-Mediated C(sp3 )-H Heteroarylation via Radical-Polar Crossover in Batch and Flow.

Photocatalytic hydrogen atom transfer is a very powerful strategy for the regioselective C(sp3 )-H functionalization of organic molecules. Herein, we report on the unprecedented combination of decatungstate hydrogen atom transfer photocatalysis with the oxidative radical-polar crossover concept to access the direct net-oxidative C(sp3 )-H heteroarylation. The present methodology demonstrates a high functional group tolerance (40 examples) and is scalable when using continuous-flow reactor technology. The developed protocol is also amenable to the late-stage functionalization of biologically relevant molecules such as stanozolol, (-)-ambroxide, podophyllotoxin, and dideoxyribose.

Merging Photocatalysis with Electrochemistry: The Dawn of a new Alliance in Organic Synthesis.

The merging of a homogeneous photocatalytic system with an electrochemical cell, having exchanged electrons as the only common point, has been recently demonstrated. This combination opens unexplored pathways in synthesis and allowed net-oxidative photocatalytic processes to be realized in the absence of a chemical oxidant, including: 1) the C-H alkylation of heteroarenes and 2) the coupling of azoles with arenes in the presence of an electrogenerated photocatalyst.

Vinylpyridines as Building Blocks for the Photocatalyzed Synthesis of Alkylpyridines.

The photocatalyzed addition of several hydrogen donors (ethers, aldehydes, alkanes, amides) onto vinylpyridines was achieved. This approach provided access to alkylpyridines, which are important building blocks for the preparation of compounds with biological activity. The strategy was very simple and straightforward because it required only a small amount of a cheap decatungstate salt as photocatalyst. As an added advantage, the reaction could be performed under sunlight irradiation as well as under flow conditions.

Hydrogen Atom Transfer (HAT): A Versatile Strategy for Substrate Activation in Photocatalyzed Organic Synthesis.

The adoption of hydrogen atom transfer (HAT) in a photocatalytic approach, in which an excited catalyst is responsible for substrate activation, offers unique opportunities in organic synthesis, enabling the straightforward activation of R-H (R = C, Si, S) bonds in desired reagents. Either a direct strategy, based on the intrinsic reactivity of a limited number of photocatalysts in the excited state, or an indirect one, in which a photocatalytic cycle is used for the generation of a thermal hydrogen abstractor, can be exploited. This microreview summarizes the most recent advances (mainly from the last two years) in this rapidly developing area of research, collecting the selected examples according to the nature of the species promoting the HAT process. From the synthetic point of view, this area has led to the development of a plethora of strategies for C-C, C-Si, C-N, C-S, and C-halogen (particularly, fluorine) bond formation, as well as for oxidation reactions.

Smooth Photocatalyzed Benzylation of Electrophilic Olefins via Decarboxylation of Arylacetic Acids.

Arylacetic acids were used as sources of benzyl radicals under tetrabutylammonium decatungstate photocatalyzed conditions for the benzylation of electron-poor olefins. The reaction proceeds smoothly in a mixed aqueous medium (MeCN/H2O 2/1) in the presence of NaHCO3, NaClO4, and an electron transfer agent (biphenyl). The reaction tolerates a wide variety of functional groups on the aromatic ring (whether electron donating or electron withdrawing) and can be extended to heteroaromatic analogues. The olefins have the double role of radical trap and electron acceptor. The present approach can also be extended to arylpropionic acids (including the nonsteroidal anti-inflammatory drugs ibuprofen and flurbiprofen), as well as mandelic acid derivatives.

Photoinduced Intermolecular Radical Hydroalkylation of Olefins via Ligated Boryl Radicals-Mediated Halogen Atom Transfer.

Light-mediated Halogen-Atom Transfer (XAT) has become a significant methodology in contemporary synthesis. Unlike α-aminoalkyl and silyl radicals, ligated boryl radicals (LBRs) have not been extensively explored as halogen atom abstractors. In this study, we introduce NHC-ligated boranes as optimal radical chain carriers for the intermolecular reductive radical hydroalkylation and hydroarylation of electron-deficient olefins by using direct UV-A light irradiation. DFT analysis allowed us to rationalize the critical role of the NHC ligand in facilitating efficient chain propagation.

Visible light-induced halogen-atom transfer by N-heterocyclic carbene-ligated boryl radicals for diastereoselective C(sp3)-C(sp2) bond formation.

Photoinduced halogen-atom transfer (XAT) has rapidly emerged as a programmable approach to generate carbon-centered radical intermediates, mainly relying on silyl and α-aminoalkyl radicals as halogen abstractors. More recently, ligated boryl radicals have also been proposed as effective halogen abstractors under visible-light irradiation. In this study, we describe the use of this approach to enable C(sp3)-C(sp2) bond formation via radical addition of carbon-centered radicals generated via XAT onto chloroalkynes. Our mechanistic investigation reveals a complex interplay of highly reactive radical intermediates which, under optimized conditions, delivered the targeted vinyl chlorides in excellent yields and Z : E ratios. Finally, we demonstrated the synthetic value of these products in transition metal-based cross-coupling reactions.

Modular synthesis of congested ß2,2-amino acids via the merger of photocatalysis and oxidative functionalisations.

A two-step protocol for the modular synthesis of ß2- and α-quaternary ß2,2-amino acid derivatives is reported. The key steps are a photocatalytic hydroalkylation reaction, followed by an oxidative functionalisation to access N-protected ß-amino acids, esters, and amides. This strategy can be effectively scaled up via continuous-flow technology.

Rapid and scalable photocatalytic C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling of aryl bromides with alkyl boranes.

In recent years, there has been a growing demand for drug design approaches that incorporate a higher number of sp3-hybridized carbons, necessitating the development of innovative cross-coupling strategies to reliably introduce aliphatic fragments. Here, we present a powerful approach for the light-mediated B-alkyl Suzuki-Miyaura cross-coupling between alkyl boranes and aryl bromides. Alkyl boranes were easily generated via hydroboration from readily available alkenes, exhibiting excellent regioselectivity and enabling the selective transfer of a diverse range of primary alkyl fragments onto the arene ring under photocatalytic conditions. This methodology eliminates the need for expensive catalytic systems and sensitive organometallic compounds, operating efficiently at room temperature within just 30 min. We further demonstrate the translation of the present protocol to continuous-flow conditions, enhancing scalability, safety, and overall efficiency of the method. This versatile approach offers significant potential for accelerating drug discovery efforts by enabling the introduction of complex aliphatic fragments in a straightforward and reliable manner.

A field guide to flow chemistry for synthetic organic chemists.

Flow chemistry has unlocked a world of possibilities for the synthetic community, but the idea that it is a mysterious "black box" needs to go. In this review, we show that several of the benefits of microreactor technology can be exploited to push the boundaries in organic synthesis and to unleash unique reactivity and selectivity. By "lifting the veil" on some of the governing principles behind the observed trends, we hope that this review will serve as a useful field guide for those interested in diving into flow chemistry.

Modular allylation of C(sp3)-H bonds by combining decatungstate photocatalysis and HWE olefination in flow.

The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, furnishing a rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp3)-H bonds. Our sequence features the merger of two distinct steps to accomplish this goal, including a photocatalytic Hydrogen Atom Transfer and an ensuing Horner-Wadsworth-Emmons (HWE) reaction. This practical protocol enables the modular and scalable allylation of valuable building blocks and has been applied to structurally complex molecules.

Accelerated and Scalable C(sp3)-H Amination via Decatungstate Photocatalysis Using a Flow Photoreactor Equipped with High-Intensity LEDs.

Carbon-nitrogen bonds are ubiquitous in biologically active compounds, prompting synthetic chemists to design various methodologies for their preparation. Arguably, the ideal synthetic approach is to be able to directly convert omnipresent C-H bonds in organic molecules, enabling even late-stage functionalization of complex organic scaffolds. While this approach has been thoroughly investigated for C(sp2)-H bonds, only few examples have been reported for the direct amination of aliphatic C(sp3)-H bonds. Herein, we report the use of a newly developed flow photoreactor equipped with high intensity chip-on-board LED technology (144 W optical power) to trigger the regioselective and scalable C(sp3)-H amination via decatungstate photocatalysis. This high-intensity reactor platform enables simultaneously fast results gathering and scalability in a single device, thus bridging the gap between academic discovery (mmol scale) and industrial production (>2 kg/day productivity). The photocatalytic transformation is amenable to the conversion of both activated and nonactivated hydrocarbons, leading to protected hydrazine products by reaction with azodicarboxylates. We further validated the robustness of our manifold by designing telescoped flow approaches for the synthesis of pyrazoles, phthalazinones and free amines.

The Merger of Benzophenone HAT Photocatalysis and Silyl Radical-Induced XAT Enables Both Nickel-Catalyzed Cross-Electrophile Coupling and 1,2-Dicarbofunctionalization of Olefins.

A strategy for both cross-electrophile coupling and 1,2-dicarbofunctionalization of olefins has been developed. Carbon-centered radicals are generated from alkyl bromides by merging benzophenone hydrogen atom transfer (HAT) photocatalysis and silyl radical-induced halogen atom transfer (XAT) and are subsequently intercepted by a nickel catalyst to forge the targeted C(sp3)-C(sp2) and C(sp3)-C(sp3) bonds. The mild protocol is fast and scalable using flow technology, displays broad functional group tolerance, and is amenable to a wide variety of medicinally relevant moieties. Mechanistic investigations reveal that the ketone catalyst, upon photoexcitation, is responsible for the direct activation of the silicon-based XAT reagent (HAT-mediated XAT) that furnishes the targeted alkyl radical and is ultimately involved in the turnover of the nickel catalytic cycle.

Decatungstate as Direct Hydrogen Atom Transfer Photocatalyst for SOMOphilic Alkynylation.

A versatile approach for the alkynylation of a variety of aliphatic hydrogen donors, including alkanes, is reported. We used tetrabutylammonium decatungstate as photocatalyst to generate organoradicals from C-H/Si-H bonds via hydrogen atom transfer. The latter intermediates underwent SOMOphilic alkynylation by methanesulfonyl alkynes to afford internal alkynes upon loss of a sulfonyl radical. The effect of different radicofugal groups on the reaction outcome was evaluated and rationalized via a combined experimental and computational approach.

Photoelectrochemical cross-dehydrogenative coupling of benzothiazoles with strong aliphatic C-H bonds.

A photoelectrochemical strategy for the cross-dehydrogenative coupling of unactivated aliphatic hydrogen donors (e.g. alkanes) with benzothiazoles is reported. We used tetrabutylammonium decatungstate as the photocatalyst to activate strong C(sp3)-H bonds in the chosen substrates, while electrochemistry scavenged the extra electrons.